Traumatic Brain Injury, Chronic Traumatic Encephalopathy, and Alzheimer Disease.

Traumatic brain injury (TBI) is a major health and economic burden. With increasing aging population, this issue is expected to continue to rise. Neurodegenerative disorders are more common with aging population in general regardless of history of TBI. Recent evidence continues to support a relation between a TBI and neurocognitive decline later in life (such as in athletes and military). This article summarizes the pathologic and clinical effects of TBI (regardless of severity) on the later development of dementia in individuals 65 years or older.

Empathy changes in neurocognitive disorders: A review.

BACKGROUND: Empathy can be broadly defined as the ability to understand what others feel (cognitive empathy) and feel what others feel (affective empathy). The capacity to empathize may be impaired in certain major neurocognitive disorders (MNCDs), affecting not only the patient, but also the caregivers. METHODS: PubMed and Google Scholar databases were searched for studies investigating empathy changes, using an objective scale, in patients with MNCDs. RESULTS: The Interpersonal Reactivity Index was most commonly used to evaluate empathy in this population. Impairments in cognitive but not affective empathy were found in patients with Alzheimer's disease (AD), and may be attributable to overall cognitive decline. Patients with frontotemporal dementia (FTD) have demonstrated severe deficits in empathy, correlating with greater caregiver burden. Empathy changes in patients with dementia with Lewy bodies, vascular dementia, and Parkinson's disease dementia have not yet been studied. Intranasal oxytocin has emerged as a promising therapeutic approach for empathy loss, but it has not been explored yet in patients with MNCDs. CONCLUSIONS: Caregivers need to be educated about empathy loss, which is an important part of the disease process in AD and FTD. Future research should further assess empathy changes in other MNCDs, as well as explore novel treatment options in this field.

Evidence-based path to newborn screening for Duchenne muscular dystrophy.

OBJECTIVE: Creatine kinase (CK) levels are increased on dried blood spots in newborns related to the birthing process. As a marker for newborn screening, CK in Duchenne muscular dystrophy (DMD) results in false-positive testing. In this report, we introduce a 2-tier system using the dried blood spot to first assess CK with follow-up DMD gene testing. METHODS: A fluorometric assay based upon the enzymatic transphosphorylation of adenosine diphosphate to adenosine triphosphate was used to measure CK activity. Preliminary studies established a population-based range of CK in newborns using 30,547 deidentified anonymous dried blood spot samples. Mutation analysis used genomic DNA extracted from the dried blood spot followed by whole genome amplification with assessment of single-/multiexon deletions/duplications in the DMD gene using multiplex ligation-dependent probe amplification. RESULTS: DMD gene mutations (all exonic deletions) were found in 6 of 37,649 newborn male subjects, all of whom had CK levels>2,000U/l. In 3 newborns with CK>2,000U/l in whom DMD gene abnormalities were not found, we identified limb-girdle muscular dystrophy gene mutations affecting DYSF, SGCB, and FKRP. INTERPRETATION: A 2-tier system of analysis for newborn screening for DMD has been established. This path for newborn screening fits our health care system, minimizes false-positive testing, and uses predetermined levels of CK on dried blood spots to predict DMD gene mutations.

Childhood onset of limb-girdle muscular dystrophy.

Limb-girdle muscular dystrophies comprise a rare heterogeneous group of genetic muscular dystrophies, involving 15 autosomal recessive subtypes and seven autosomal dominant subtypes. Autosomal recessive dystrophy is far more common than autosomal dominant dystrophy. Typical clinical features include progressive limb muscle weakness and atrophy (proximal greater than distal), varying from very mild to severe. Significant overlap of clinical phenotypes, with genetic and clinical heterogeneity, constitutes the rule for this group of diseases. Muscle biopsies are useful for histopathologic and immunolabeling studies, and DNA analysis is the gold standard to establish the specific form of muscular dystrophy. A definitive diagnosis among various subtypes is challenging, and the data presented here provide neuromuscular clinicians with additional information to help attain that goal.

Impaired myocardial perfusion reserve and fibrosis in Friedreich ataxia: a mitochondrial cardiomyopathy with metabolic syndrome.

AIMS: Cardiomyopathy produces significant mortality in patients with Friedreich ataxia (FA), a genetic disorder that produces intra-mitochondrial iron accumulation. We sought to test the hypothesis that abnormal myocardial perfusion reserve and fibrosis represent early manifestations of cardiomyopathy. METHODS AND RESULTS: Twenty-six patients with genetically proven FA ages 36 ± 12 years without cardiomyopathy and eight controls underwent cardiac magnetic resonance with adenosine. Precontrast imaging for myocardial iron estimation was performed. Myocardial perfusion reserve index (MPRI) was quantified using the normalized upslope of myocardial enhancement during vasodilator stress vs. rest. Left ventricular (LV) mass and volumes were computed from short-axis cine images. Serologies included lipids, and platelets were isolated for iron quantification using inductively coupled plasma mass spectrometry. Left ventricular ejection fraction and mass averaged 64.1 ± 8.3% and 62.7 ± 16.7 g/m², respectively, indicating preserved systolic function and absence of significant hypertrophy. Myocardial perfusion reserve index quantification revealed significantly lower endocardial-to-epicardial perfusion reserve in patients vs. controls (0.80 ± 0.18 vs. 1.22 ± 0.36, P = 0.01). Lower MPRI was predicted by increased number of metabolic syndrome (met-S) features (P < 0.01). Worse concentric remodelling occurred with increased GAA repeat length (r = 0.64, P < 0.001). Peripheral platelet iron measurement showed no distinction between patients and controls (5.4 ± 8.5 × 10⁻7 vs. 5.5 ± 2.9 × 10⁻7 ng/platelet, P = 0.88), nor did myocardial T2* measures. CONCLUSIONS: Patients with FA have abnormal myocardial perfusion reserve that parallels met-S severity. Impaired perfusion reserve and fibrosis occur in the absence of significant hypertrophy and prior to clinical heart failure, providing potential therapeutic targets for stage B cardiomyopathy in FA and related myocardial diseases.

Unexpected detection of dystrophin gene deletions by array comparative genomic hybridization.

Array comparative genomic hybridization has increasingly become the standard of care to evaluate patients for genomic imbalance. As the patient population evaluated by microarray expands, there is certain to be an increase in the detection of unexpected, yet common diseases. When array results predict a late-onset disorder or cancer predisposition, it becomes a challenge for physicians and counselors to adequately address with patients. Included in this study were three patients described with nonspecific phenotypic findings who underwent microarray testing to better define their disease etiology. An unexpected deletion within the dystrophin gene was observed in each case, despite that no patient was suspected of a dystrophinopathy at the time of testing. The patients included an 8-day-old male with a dystrophin deletion predictive of Becker muscular dystrophy, an 18-month old female found to be the carrier of deletion, and a 4-year-8-month-old male with a deletion predictive of Duchenne muscular dystrophy. In this circumstance it becomes difficult to counsel the family, as well as to predict disease course when underlying medical conditions may exist. However, early detection may enable the patient to receive proactive treatment, and allows for screening of at-risk family members. Ultimately, it is up to the clinician to promote informed decision-making within the family prior to testing, and ensure that adequate counseling is provided during follow-up.

Gentamicin-induced readthrough of stop codons in Duchenne muscular dystrophy.

OBJECTIVE: The objective of this study was to establish the feasibility of long-term gentamicin dosing to achieve stop codon readthrough and produce full-length dystrophin. Mutation suppression of stop codons, successfully achieved in the mdx mouse using gentamicin, represents an important evolving treatment strategy in Duchenne muscular dystrophy (DMD). METHODS: Two DMD cohorts received 14-day gentamicin (7.5mg/kg/day): Cohort 1 (n = 10) stop codon patients and Cohort 2 (n = 8) frameshift controls. Two additional stop codon DMD cohorts were gentamicin treated (7.5mg/kg) for 6 months: Cohort 3 (n = 12) dosed weekly and Cohort 4 (n = 4) dosed twice weekly. Pre- and post-treatment biopsies were assessed for dystrophin levels, as were clinical outcomes. RESULTS: In the 14-day study, serum creatine kinase (CK) dropped by 50%, which was not seen in frameshift DMD controls. After 6 months of gentamicin, dystrophin levels significantly increased (p = 0.027); the highest levels reached 13 to 15% of normal (1 in Cohort 3, and 2 in Cohort 4), accompanied by reduced serum CK favoring drug-induced readthrough of stop codons. This was supported by stabilization of strength and a slight increase in forced vital capacity. Pretreatment stable transcripts predicted an increase of dystrophin after gentamicin. Readthrough efficiency was not affected by the stop codon or its surrounding fourth nucleotide. In 1 subject, antigen-specific interferon-gamma enzyme-linked immunospot assay detected an immunogenic dystrophin epitope. INTERPRETATION: The results support efforts to achieve drug-induced mutation suppression of stop codons. The immunogenic epitope resulting from readthrough emphasizes the importance of monitoring T-cell immunity during clinical studies that suppress stop codons. Similar principles apply to other molecular strategies, including exon skipping and gene therapy.

Myocardial ischemia in the absence of epicardial coronary artery disease in Friedreich's ataxia.

We present the first in vivo detection of microvascular abnormality in a patient with Friedreich's ataxia (FA) without epicardial coronary artery disease using cardiac magnetic resonance (CMR). The patient had exertional chest pain and dyspnea prompting referral for cardiac evaluation. These symptoms were reproduced during intravenous adenosine infusion, and simultaneous first-pass perfusion imaging showed a significant subendocardial defect; both symptoms and perfusion deficit were absent at rest. Epicardial coronaries were free of disease by invasive angiography; together, these findings support the notion of impaired myocardial perfusion reserve in FA.